From its beginnings, organic chemistry has been a partner to biology, often crossing the artificial boundary between the sciences to the benefit of both disciplines. As the field has matured, it has continued to address matters of structure and synthesis to increasingly encompass the grand challenge of designing and preparing molecules having a particular function. All three of these come together in the pursuit of new chemical probes for use in chemical biology. This Thematic Series highlights some of the numerous ways that molecular tools inform biological research. The structural diversity of molecules that function as probes is broad indeed, some of them complex enough that even the most discerning practitioner of organic synthesis may consider them as worthy of their efforts.